Analysis of transgene-induced and spontaneous mutants in the mouse is a method of gene discovery that associates genes with physiological function and generates models of human inherited disease. The transgene-induced mutation Tg9257 disrupts fetal development of the eye, inner ear, and olfactory organs and results in vestibular dysfunction and anopthalmia. The target region for this mutation has been isolated in two overlapping BAC clones. The P.I. will identify candidate genes by sequence analysis, and compare mutant and wild type sequences to find the responsible mutation. The relationship of this gene to the pathways regulating development of sensory organs will be determined by analysis of mice with targeted mutations of other genes in the pathway. They will determine the sites of expression, subcellular localization, and developmental regulation of the 9257 genes. Dr. Meisler will also extend her analysis of dystonia in the medJ mutant of the sodium channel Scn8a. The electrophysiological mechanism will be determination of the electrophysical properties of specific populations of neurons by recordings from brain slices and dissociated cells. A modifier gene, Scnm1, that influences susceptibility to the movement disorder, will be isolated by positional cloning. The interaction between Scn8a and Scnm1 is a model for gene interactions that modify human susceptibility to inherited neurological disorders.